tbuckley/cabot-search huggingface dataset:
EXTH-70. IMMUNOTHERAPY REVERSES GLIOMA-DRIVEN DYSFUNCTION OF IMMUNE SYSTEM HOMEOSTASIS
Authors: Bayli Dean, Tyler Wildes, Joseph Dean, David Shin, Connor Francis, Mathew Sebastian, Laura Falceto Font, Ginger Moore, Brandon Wummer, Catherine Flores
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioma-induced immune disfunction has been described in a limited number of studies, and here we further demonstrate that gliomas also interrupt the cellular differentiation programming and outcomes of hematopoietic stem cells (HSC) in the bone marrow. HSCs from glioma-bearing mice are re-programmed and driven towards expansion of myeloid lineage precursors myeloid-derived suppressor cells (MDSC) in secondary lymphoid organs. However, we found this is reversed by immunotherapy. Adoptive cellular therapy (ACT) has been demonstrably efficacious in multiple preclinical models of CNS malignancies, and here we describe how glioma-induced disfunction is reversed by this immunotherapeutic platform. METHODS The impact of orthotopic KR158B glioma on HSCs was evaluated in an unbiased fashion using single cell RNAseq of lineage- cells and phenotypically using flow cytometry. Mature myeloid cell frequencies and function were also evaluated using flow cytometry. Finally, ACT containing total body irradiation, tumor-specific dendritic cells, tumor-reactive T cells, and HSCs isolated from glioma-bearing or non-tumor-bearing mice was used to evaluate cell fate differentiation and survival. RESULTS We observed differential gene expression of HSCs in tumor-bearing versus healthy mice coupled with an expansion of myeloid lineage subsets in glioma-bearing mice. Interestingly, MDSCs from glioma-bearing mice demonstrated hyper suppressive capacity as compared to MDSCs from non-tumor-bearing hosts. Interestingly, treatment with ACT overcame the suppressive properties of glioma-bearing HSCs. When HSCs from tumor-bearing mice were transferred with ACT, we observed significant survival benefit and long-term cures in orthotopic glioma models compared with mice treated with ACT using non-glioma-bearing HSPCs. CONCLUSIONS These findings demonstrate the suppressive disposition in HSCs from glioma-bearing hosts can be redirected using ACT for significant survival benefit. Collectively, these data demonstrate gliomas impact the hematopoietic compartment at the progenitor level to promote expansion of suppressive myeloid cells and their progenitors. However, ACT can overcome this bias and provide lasting anti-tumor effects.
NIMG-04. LONGITUDINAL TRACKING OF PERITUMORAL EDEMA VOLUME USING PACS-INTEGRATED TOOLS PROVIDES CRITICAL INFORMATION IN TREATMENT ASSESSMENT OF NSCLC BRAIN METASTASES AFTER RADIOSURGERY
Authors: Manpreet Kaur, Gabriel Cassinelli Petersen, Marc von Reppert, Leon Jekel, Irene Dixe oliveira de Santo, Sunitha Varghese, Veronica Chiang, Mariam Aboian
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Brain metastases (BM) are the most common intracranial malignancies in adults and mostly originate from lung cancer. Gamma Knife (GK) has become standard of care for BM, however there is insufficient knowledge of the posttreatment volumetric changes of peritumoral edema of BM due to paucity of tools for volumetric segmentation in neuroradiology practice. Recently PACS-integrated tools have become available in select clinical practices facilitating the comparison of posttreatment peritumoral edema volume changes and 2D-based measurements of CE tumor core. METHODS Patients with NSCLC BM ≥ 10 mm on T1c+ treated with GK had volumetric measurements for up to 7 follow-ups using a PACS-integrated tool that segments the FLAIR hyperintense region surrounding and including the CE lesion. The 2D and volumetric measurements were compared by creating treatment response curves with incorporation of clinical information including steroid timing. RESULTS 50 NSCLC BM were included. The median pretreatment peritumoral volume was 8.5 cm3 (IQR 1–47 cm3, n= 36). The volume significantly decreased at 0–90 days (median 1.2 cm3, IQR 0.5–6.1 cm3, n= 31) and between 0-90 and 91-180 days (median 0.8 cm3, IQR 0.3-2.3 cm3, n= 26) post-GK. The time of peak median peritumoral volume increase was at &amp;gt; 365 days (median 1.4 cm3, IQR 0.4–8.1 cm3, n= 19). There was a positive correlation between longest diameter (LD) and peritumoral edema volume (rs= .75, p&amp;lt; .05). At 181–270 days post-GK 50% of BM showed incongruent response course for LD and peritumoral edema volume. The congruence/incongruence ratio of edema/enhancing portion of BM changed over follow-up time. CONCLUSION Half of the BM in our study did not show congruent response when comparing posttreatment peritumoral edema volume course to CE lesions in longitudinal assessment. Therefore, there is a critical need for quantitative tools that are incorporated into clinical practice to assess peritumoral edema treatment response.
SURG-30. SURGICAL MANAGEMENT OF A RARE SACROCOCCYGEAL MYXOPAPILLARY EPENDYMOMA OF THE GLUTEAL REGION: CASE ILLUSTRATION AND SYSTEMATIC LITERATURE REVIEW
Authors: Nolan Brown, Brian Lien, Alexander Himstead, Benjamin Ball, Frank Hsu
Journal: Neuro-Oncology (2022)

Abstract Ependymomas are rare tumors originating from neuroepithelial cells lining the wall of the ventricles or central canal of the spinal cord. While these tumors mainly occur within the central nervous system (CNS), there are occasional reports in children and young adult patients with a primary tumor occurrence outside of the CNS. Ependymomas of the sacrococcygeal region have been infrequently described in the literature with no standard of care established. We present a case report and review of the literature regarding this rare entity. A 24-year-old woman presented with right gluteal pain worsened by sitting and a palpable soft tissue mass of the sacrococcygeal region. Magnetic resonance imaging revealed a 3.7 cm cystic mass centered in the right gluteal region. Histology revealed myxopapillary ependymoma. The patient underwent an interdisciplinary neurosurgical and orthopedic oncology en bloc resection of the ependymoma, which intraoperatively appeared to originate from the coccygeal nerve. Through our systematic literature review, we identified 38 studies describing 78 unique cases of myxopapillary ependymoma occurring in the sacrococcygeal region without extension into the CNS. The exact presentation of sacrococcygeal ependymomas is variable. Given their location and propensity for drainage, they are frequently misdiagnosed as pilonidal cyst. Recurrence occured in 16.7% of cases described, typically within 20 years. Rate of metastasis was 20%. The primary means of management for sacrococcygeal myxopapillary ependymoma is complete surgical resection including excision of the neighboring sacrum or coccyx, when involved. Ultimately, we demonstrate that a myxopapillary ependymoma may present as an isolated gluteal mass attached to the coccygeal nerve, without frank CNS involvement. Furthermore, an interdisciplinary approach to surgical resection of this lesion appears to represent an effective treatment modality.
TMIC-52. RELATIONSHIP BETWEEN MACROPHAGE AND RADIOSENSITIVITY IN HUMAN PRIMARY AND RECURRENT GLIOBLASTOMA: IN SILICO ANALYSIS WITH PUBLICLY AVAILABLE DATASETS
Authors: In Ah Kim, Bum Sup Jang
Journal: Neuro-Oncology (2022)

Abstract The glioblastoma microenvironment predominantly contains tumor-associated macrophages that support tumor growth and invasion. We investigated the relationship between tumor radiosensitivity and infiltrating M1/M2 macrophage profiles in public datasets of primary and recurrent glioblastoma. We estimated the radiosensitivity index (RSI) score based on gene expression rankings. Macrophages were profiled using the deconvolution algorithm CIBERSORTx. Samples from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), the Ivy Glioblastoma Atlas Project dataset, a single-cell RNA sequencing dataset (GSE84465), Glioma Longitudinal Analysis Consortium (GLASS), and an immunotherapy trial dataset (GSE121810) were included. RSI-high radioresistant tumors were associated with worse overall survival in TCGA and CGGA than RSI-low tumors. M1/M2 macrophage ratios and RSI scores were inversely associated, indicating that radioresistant glioblastoma tumor microenvironments contain more M2 than M1 macrophages. In the single-cell RNA sequencing dataset, the mean RSI of neoplastic cells was positively correlated with high M2 macrophages proportions. A favorable response to programmed cell death protein 1 (PD-1) therapy was observed in recurrent glioblastomas with high M1/M2 macrophage ratios and low RSI scores. In patients with recurrent glioblastoma, fewer M2 macrophages and low RSI scores were associated with improved overall survival. High M2 macrophage proportions may be involved in radioresistant glioblastoma.
DDDR-01. AZD9574 IS A NOVEL, BRAIN PENETRANT PARP-1 SELECTIVE INHIBITOR WITH ACTIVITY IN AN INTRACRANIAL XENOGRAFT MODEL OF TRIPLE NEGATIVE BREAST CARCINOMA WITH HOMOLOGOUS RECOMBINATION REPAIR DEFICIENCY
Authors: Kunzah Jamal, Anna Staniszewska, Jacob Gordon, Domenic Pilger, Giuditta Illuzzi, Joanne Wilson, Aaron Smith, Eric Gosselin, Lisa McWilliams, Shenghua Wen, Frank McGrath, Gregory Dowdell, Dominic Kabbabe, Matthew Griffin, Barry Davies, Petra Hamerlik, Magnus Schou, Andy Pike, Jeffrey Johannes
Journal: Neuro-Oncology (2022)

Abstract The Poly (ADP-ribose) polymerase (PARP) family has numerous essential functions in cellular processes such as transcription, chromatin remodelling, DNA damage response and repair as well as apoptosis. PARP inhibition blocks base excision repair and results in conversion of SSBs to DNA double-strand break (DSBs), the most deleterious form of DNA damage. DSBs can be repaired by homologous recombination repair (HRR) or non-homologous end joining (NHEJ). The physiological importance of HRR is underscored by the observation of genomic instability in HRR-deficient (HRD+) cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HRR genes. PARP1 and PARP2 are required for SSB repair, while PARP1 is also involved in the repair of DNA double-strand breaks (DSBs) and replication fork damage. AZD9574 is a novel brain penetrant PARP1 inhibitor that acts by selectively inhibiting and trapping PARP1 at the sites of SSBs. While AZD9574 inhibited PARP1 enzymatic activity in all tested cell lines irrespective of the HRR status (IC50 range between 0.3 – 2 nM), colony formation assay in isogenic cell lines pairs confirmed higher potency and selectivity towards HRD+ models. In vivo, AZD9574 demonstrated dose-dependent efficacy in a BRCA1 mutant MDA-MB-436 subcutaneous xenograft model. Anti-tumour effects of AZD9574 were manifested by significant growth regressions that were durable after treatment withdrawal. An intracranial xenograft model of breast cancer brain metastases was developed to assess the efficacy of AZD9574 in the context of blood-brain barrier penetrance. Treatment of animals with established intracranial lesions showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.This abstract was previously presented at AACR 2022 (Hamerlik et al, AACR 2022, Abs #3880)
RADT-20. REPORT OF THE RESPECT-GBM™ PHASE I/IIA DOSE ESCALATION TRIAL OF RHENIUM-186 NANOLIPOSOME (186RNL) IN RECURRENT GLIOMA VIA CONVECTION ENHANCED DELIVERY (CED) &amp; PLANNED PHASE IIB TRIAL
Authors: Andrew Brenner, William Phillips, Ande Bao, Marc Hedrick, Norman LaFrance, Joel Michalek, Toral Patel, Jeffrey Weinberg, John Floyd
Journal: Neuro-Oncology (2022)

Abstract A phase I/IIa dose escalation trial was initiated to determine the safety and recommended phase II dose (RP2D) of 186RNL in patients with recurrent glioma. Liposomal rhenium-186 (186RNL) is a source of high energy beta particles and gamma photons with attractive properties for brain CED.Patients with biopsy proven recurrent glioma had computerized treatment planning and placement of up to 4 intracranial catheter(s). Each patient received a single administration of 186RNL by CED. Whole body planar and SPECT/CT imaging from days 1-8 following treatment was performed. Patients were followed for safety, sufficiency of delivery and overall survival. Twenty-one patients across 6 dose escalation cohorts received 1.0-22.3mCi in a volume of 0.6-8.8mL. Mean tumor volume was 8.3mL, patients were heavily pretreated (mean 1.7 recurrences) with poor prognostic factors. There were no CED failures. Mean absorbed radiation dose to the tumor (MARDT) was 271Gy. No dose limiting toxicities were observed. Patients were stratified by MARDT. Those receiving &amp;gt; 100Gy MARDT (n=12) had a median and mean overall survival of 129.9 (95% CI 35.1 to 169.3) and 99.5 ± 19 weeks respectively with 3 patients alive. Patients receiving ≤ 100Gy MARDT (n=9) had a median and mean overall survival of 22.4 (95% CI 6.6 to 45.4) and 24.7 ± 4.8 weeks respectively, none are alive. Kaplan Meier analysis of overall survival for patients receiving MARDT greater than 100Gy vs. those with ≤ 100Gy showed a statistically significant difference in overall survival (p&amp;lt; 0.001).A single administration of 186RNL by CED in recurrent glioma patients is feasible, safe, and potentially effective in increasing overall survival when &amp;gt; 100Gy radiation is delivered to the tumor. A RP2D of 22.3mCi in 8.8mL was selected for patients with tumor size of ≤ 15mL in the planned phase 2b trial. The PIIb trial design and comparative survival data will also be presented.
CNSC-21. CHARACTERIZATION OF NEURON-TUMOR INTERACTIONS USING HUMAN CO-CULTURES
Authors: Svenja Tetzlaff, Joaquín Campos, Linh Nguyen, Christopher Strahle, Wolfgang Wick, Thomas Kuner, Frank Winkler, Claudio Acuna, Varun Venkataramani
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma are incurable brain tumors characterized by their colonization of the entire brain and their notorious therapeutic resistance. Recently, we discovered long membrane tubes called tumor microtubes contributing to invasion, network formation of tumor-tumor networks and therapeutic resistance. Subsequently, heterogeneous networks of neurons and glioblastoma cells were characterized, which can communicate by synaptic and perisynaptic contacts as well as by paracrine mechanisms. Currently used models of studying neuron-glioblastoma interactions are limited by the possibility to study glioblastoma in a defined human neuronal microenvironment. Here, we set out to derive excitatory and inhibitory neurons from embryonic stem cells via lentiviral reprogramming and co-cultured them with patient-derived glioblastoma cells. We could show that structural and functional neuron-glioblastoma synaptic contacts are formed. Functional communication between neurons and glioblastoma cells were characterized with calcium imaging, showing similar complex calcium dynamics previously characterized with in vivo imaging of patient-derived xenograft models. The single-cell glioblastoma morphology was morphometrically similar to that of human glioblastoma tissue. Tumor microtubes and the formation of tumor-tumor networks could be demonstrated. Additionally, glioblastoma invasion patterns in our human neuronal co-culture model resemble invasion patterns recently characterized with patient-derived xenograft models. Lastly, we investigated reciprocal neuron-glioblastoma interactions and longitudinally characterized neuronal activity with patch-clamp electrophysiology. In conclusion, we provide a novel human neuron-glioblastoma co-culture system allowing in-depth molecular and functional characterization for future Cancer Neuroscience studies.
CTNI-60. PRELIMINARY RESULTS OF BINIMETINIB AND ENCORAFENIB IN ADULTS WITH RECURRENT BRAF V600E-MUTATED HIGH-GRADE GLIOMA
Authors: Karisa Schreck, Roy Strowd, L Burt Nabors, Ben Ellingson, Joy Fisher, Serena Desideri, Neeraja Danda, Michelle Rudek, Stuart Grossman, Xiaobu Ye
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Although &amp;lt; 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are being identified more frequently as genetic testing increases in gliomas. Given the treatment-refractory nature HGG, RAF-targeted therapy is of special interest. The combination of encorafenib (BRAF inhibitor) with binimetinib (MEK inhibitor) was evaluated in adults with recurrent BRAFV600-mutated HGG. METHODS In this phase 2, open-label, Adult Brain Tumor Consortium trial(NCT03973918) encorafenib (450mg daily) and binimetinib (45mg twice daily) were administered continuously until disease progression, unacceptable toxicity, or death. Eligible patients had a histologically-confirmed HGG with BRAF-V600E mutation identified by PCR or next generation sequencing, and had progressed after radiation and any number of prior medical therapies. The primary endpoint was radiographic response rate by RANO criteria. Plasma was collected at baseline, on-study, and at progression for correlatives. RESULTS Five patients enrolled between January 2020 and November 2021. All patients had at least one prior recurrence (range 1-4) and received radiation one or more times. Median age was 27 years(range 22-77). Histopathologic diagnosis was glioblastoma(n = 2), anaplastic PXA(aPXA; n = 2), and anaplastic ganglioglioma(aGG; n = 1). Patients received treatment for 2-28months; currently 2/5 patients remain on treatment (8 and 30 months). Radiographic response rate was 60%(3/5): CR in two (glioblastoma, treated 10months; glioblastoma, 8months treatment ongoing), PR in one (aPXA, 28months treatment ongoing), SD in one (aGG, treated 3months), and PD in one (aPXA, treated 2months). Likely attributable adverse events (CTCAE grade ≥ 3) included cilioretinal artery occlusion (came off study) and asymptomatic elevated CPK. Analysis of paired plasma samples and correlation with response is ongoing. CONCLUSIONS Encorafenib and binimetinib demonstrate promising tumor responses in patients with recurrent BRAFV600E-mutated HGG with sustained responses in all GBM and 50% of aPXA in this small series, warranting careful consideration in this rare tumor subgroup. This Phase 2 study has closed due to enrollment issues
QOL-01. RISK FACTORS FOR AND CONSEQUENCES OF PROLONGED DEXAMETHASONE USE IN PATIENTS WITH GLIOBLASTOMA (GBM)
Authors: Laura Donovan, Adela Joanta-Gomez, Julia Furnari, Brandi Mouton, Andrew Lassman
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Dexamethasone is the primary treatment for tumor-associated edema. Prolonged use can have significant side effects and may negatively impact survival in GBM. Factors associated with steroid dependence and steroid associated side effects (SASEs) are not well established. METHODS We performed a retrospective study of patients with newly diagnosed, IDH-wildtype GBM at our center. Demographics, clinical and tumor characteristics, dexamethasone usage, and SASEs (infections, myopathy, hypertension, fractures, mood symptoms, weight gain, and hyperglycemia) were extracted through chart review. We compared survival outcomes (OS) between patients with and without steroid dependence. Risk factors for steroid dependence were identified through logistic regression analysis. RESULTS 39/92 (35.9%) patients developed steroid dependence. Of these, 26/39 (66.7%) were on steroids at the start of initial treatment. Patients who developed steroid dependence were older, more likely to have STR/biopsy, bilateral disease, KPS &amp;lt; 90, baseline neurological deficits, and to be obese (BMI ≥ 30). 94.9% of patients with steroid dependence experienced ≥ 1 SASE (vs. 34%) and 46.2% experienced ≥ 3 SASEs (vs. 3.8%). Mood symptoms (69.2% vs. 26.4%), hyperglycemia (53.8% vs. 7.5%) and infections (51.3% vs. 7.5%) were the most common SASEs. Median OS was inferior in steroid-dependent patients (18 vs 25 mo). Baseline obesity was identified as a risk factor for developing steroid dependence (OR 5.9). DISCUSSION SASEs are common in patients on prolonged steroids. Obesity may increase the risk of developing steroid dependence. Identifying patients at highest risk for steroid dependence may help guide future interventions to mitigate the negative effects of prolonged dexamethasone use.
SURG-14. LOWER-GRADE GLIOMA IN ELDERLY PATIENTS: TREATMENT AND OUTCOMES IN A MOLECULARLY CHARACTERIZED CONTEMPORARY COHORT
Authors: Christine Jungk, Mara Gluszak, Philip Dao Trong, Andreas von Deimling, Christel Herold-Mende, Unterberg Andreas
Journal: Neuro-Oncology (2022)

Abstract Lower-grade glioma (LGG) is rare among patients above the age of 60. Previous series reported poor outcomes, likely due to a high proportion of missed IDH wildtype astrocytomas which today would be diagnosed as glioblastoma, and thus proposed defensive treatment in elderly patients. We questioned these findings in our contemporary cohort of “true” LGGs, i.e. IDH mutant astrocytoma and oligodendroglioma WHO grade 2 and 3. Patients aged 60 years and older (“elderly”) treated for hemispheric LGG were retrospectively analyzed for demographic, tumor- and treatment-related factors and progression-free survival (PFS) and were compared to a cohort of patients younger than 60 years. Inclusion criteria, amongst others, were availability of molecular data and volumetric assessment of pre- and postoperative tumor burden. 212 patients were analyzed, among those 21 elderlies (9.9%). Elderly patients did not differ from younger ones regarding preoperative tumor volumes, eloquent location, presence of contrast enhancement and clinical presentation (seizures, focal deficits). In both groups (elderly vs. younger), most patients underwent tumor resection (81% vs. 90.6%; p=0.25) with comparable median residual tumor volumes (5.12 cm3 vs. 3.28 cm3; p=0.66). There was a trend towards more aggressive surgical approaches in younger patients, e.g., use of IOM and awake surgery. However, rates of functional deterioration (p=0.2) and revision surgery (p=0.98) were comparable. Oligodendroglioma, in relation to astrocytoma, was more common in the elderly (76.2% vs. 46.1%; p=0.011). Adjuvant radio- and/or chemotherapy was administered in 76.2% of elderly and 59.8% of younger patients (p=0.163). Median PFS was comparable (50 vs. 56 months; p=0.62), regardless of WHO grade (p=0.43) and tumor subtype (p=0.93). In conclusion, favorable surgical and survival outcomes were achieved in our series that were comparable to those of younger patients. Thus, intensified treatment including maximal safe resection should be advocated in elderly patients whenever feasible.